Pentose Cycle, Significance, Regulation

Also termed Hexose Monophosphate Pathway (HMP) or:

• Hexose Monophosphate Shunt
• Pentose Phosphate Pathway
• 6-Phosphogluconate Pathway

Functions of Pentose Phosphate Pathway

The Pentose Phosphate Pathway generates NADPH, which is required for reductive detoxification in all cells.  It also generates pentose sugars, most importantly ribose-5-phosphate for nucleotide synthesis, which is essential for DNA and RNA synthesis. It is involved in the interconversions of dietary carbohydrates into glycolytic/gluconeogenic intermediates. It converts unused intermediates to fructose-6-phosphate and glyceraldehyde-3-phosphate for the glycolytic pathway.  The enzymes of the pentose cycle reside in the cytosol and are present in all cells. It is divided into two phases, in the cytosol includes an irreversible oxidative phase, followed by a series of reversible sugar–phosphate interconversions. The precursor of this pathway, is glucose-6-phosphate.

To sum up, the pathway generates:

• NADPH
• Ribose-5-phoshpate
• Glycolytic intermediates: Fructose-6-phosphate and Glyceraldehyde-3-phosphate

Oxidative Phase of the Pentose Phosphate Pathway

The oxidative phase of the pentose phosphate pathway generates ribulose-5-phosphate while yielding 2 NADPH molecules per glucose molecule. Glucose-6-phosphate dehydrogenase oxidizes the aldehyde at carbon 1 of G-6-P and reduces NADP+ to NADPH. Next, another oxidation reaction takes place as 6-phosphogluconate dehydrogenase releases a carboxyl group as CO2 and yields another NADPH. Ribulose-5-phosphate is produced.

Oxidative Phase of Pentose Phosphate Pathway

Enzymes numbered:

• 1 = glucose 6-phosphate dehydrogenase (G6PDH),- rate limiting enzyme. This is the rate limiting committed step.
• 2 = 6-phosphogluconolactone hydrolase (lactonase)
• 3 = 6-phosphogluconate dehydrogenase.

Summary: Oxidative Phase

• Reduction of NADP+ → NADPH + H+ (2)
• A decarboxylation, yielding 1 CO₂
• The product is ribulose-5-phosphate

Significance of NADPH in different tissue:

1. Erythrocytes:  Erythrocytes use NADPH to reduce glutathione disulfide to glutathione glutathione helps neutralize oxidative stress from oxygen transport. This protects against oxidative damage.
2. Liver, Adipose tissue, Lactating mammary glands - NADPH provided for fatty acid biosynthesis
3. Adrenal cortex, Ovaries, Testes, Placenta - NADPH provided for synthesis of steroid hormones - hydroxylation reactions
4. White blood cells and macrophages - NADPH provided for killing phagocytosed bacteria.
5. Thyroid - NADPH as a coenzyme for the synthesis of thyroid hormone.

Non-Oxidative Phase of the Pentose Phosphate Pathway

Non-oxidative phase of pentose phosphate pathway.

The non-oxidative phase of the pentose phosphate pathway initially converts ribulose-5-phosphate to ribose-5-phosphate. This is an isomerization reaction (a ketose to aldose conversion similar to the one in which fructose-6-phosphate is isomerized to glucose-6-phosphate) carried by isomerase.

Ribose-5-phosphate can either: depending on the needs of the cell

1. Enter the pathway for nucleotide synthesis
2. Be converted to glycolytic intermediates.

The following reactions are reversible. The enzymes involved are transketolase and transaldolase. Two carbons are transferred in transketolase reactions and three carbons are transferred in the transaldolase reaction.

• Note that in tissue that requires high NADPH, the ribose-5-phosphate is converted back to glucose-6-phosphate using non oxidative reactions so glucose-6-phosphate can re enter the oxidative phase to generate more NADPH. In this case, the focus of the pathway is the oxidative part and reactions in the non-oxidative phase are inhibited.

Regulation of Glucose 6-phosphate dehydrogenase (G6P-DH)

• Allosterically stimulated by coenzyme NADP+
• Inhibited by NADPH
• Under most metabolic conditions, the ratio of NADPH/NADP+ is high enough to inhibit G6P-DH, so that G-6P can be used to fuel glycolysis.
• With increased demand for NADPH, the ratio of NADPH/NADP+ decreases, and flux through the pathway increases in response to the enhanced activity of G6P-DH.
• Activated by Insulin – upregulation: increase of amount of enzyme & flux through the pathway increases in the absorptive state.
• If NADPH is forming faster than it is being used for biosynthesis and glutathione reduction, [NADPH] rises and inhibits G6P-DH in HMP.
• More glucose 6-phosphate then becomes available for glycolysis.

Resources

Literature

• Abali. Lippincott Illustrated Reviews: Biochemistry. Wolters Kluwer, 2021.
• Lieberman, Michael, and Alisa Peet. Marks’ Essentials of Medical Biochemistry: A Clinical Approach. Wolters Kluwer, 2015.